1. Field of the Invention
The present invention relates generally to the field of radioimmunotherapy. More specifically, the present invention relates to alpha-emitting constructs with high specific activity and their uses to kill large tumors or other cells involved in human disease states.
2. Description of the Related Art
In radiolabeled antibody therapy, an antibody/radionuclide combination that has been optimized for bulky disease is not optimal for targeting minimal disease (1). Radionuclides that emit long-range beta particles, for example, are generally considered appropriate for targeting bulky disease because their range compensates for the non-uniform antibody distribution that is typical of gross disease. These radionuclides, however, are inappropriate for targeting single cells (2-3).
Antibody forms such as fragments that penetrate solid tumor more rapidly do so at the expense of affinity. In targeting smaller, more penetrable clusters, such agents are only left with the disadvantage of reduced affinity. This is in contrast to chemotherapy wherein a greater effectiveness against bulky disease is also applicable to minimal disease. Radiolabeled antibody therapy is fundamentally different from chemotherapy in its mechanism of action. Although well-justified for chemotherapy, the “solid-tumor hurdle” is not appropriate for radioimmunotherapy (4).
To target bulky disease, intravenously administered antibody must extravasate, diffuse across an interstitial fluid space and then distribute throughout antigen positive cells (FIG. 1A). Each of these steps is associated with a barrier to delivery (5-11). By targeting hematologically distributed single tumor cells or tumor cell clusters, the barriers to antibody delivery are diminished (FIG. 1B). The apparent therapeutic dependence on cluster size and tumor burden is consistent with modeling analyses and experimental observations of antibody penetration (12).
In targeting disseminated tumor cells or micrometastases, each tumor cell must express the antigen. This seemingly severe requirement may be countered by taking advantage of the unique aspects of micrometastatic targeting. Intravenously administered antibody will not be rapidly accessible to potentially cross-reactive cells on the epithelial side of the vasculature. It is possible, therefore, to relax the requirements of antibody specificity when targeting rapidly accessible, hematologically distributed disease by using shorter-lived radionuclides which will have decayed before antibody extravasation. By relaxing the requirement for specificity, antigens that have a higher and more uniform expression on tumor cells may be selected (13).
Bismuth-213 or 212 conjugated alpha-emitting IgG ligands have been proposed to be useful in humans in killing single cells only. These ligands have not thought to be useful in killing solid tumors or small micrometastatic collections of cells only. These single cells or clusters of cells are found in the blood, bone marrow, lymph nodes, liver, and spleen or in regional collections as small metastatic deposits such as in the cerebrospinal fluid, ascites or pleural fluids of patients with leukemia and other cancers (“For Bi-213, no specific killing was observed, which is an indication for the limited applicability of this radionuclide in the treatment of solid tumors.”; 14-20). This universally held belief of the application of alpha particle emitters to single cells was based on the short path length of the alpha particles (<100 micrometers), equal to about 2-4 cell diameters and the short half-life of the nuclides (<1 hr). Because the alpha particle emitter decays largely within 3-4 hours, and the time for an IgG to diffuse into a large tumor is on the order of days, there was thought to be little possibility that an IgG carrying Bi-213 or Bi-212 could penetrate beyond 1 or 2 cells to achieve cell kill. Hence, only single cells in the blood, marrow, liver or spleen would be reasonable targets. It is for that reason that the initial studies have focused on leukemias, peritoneal metastases, cancerous meningitis in the cerebrospinal fluid, or micromestatic deposits in the bone marrow.
Strategies to use small quantities, 5-20 mCi, of Bi-213 on labeled ligands have been proposed to kill individual cells such as cancer cells. This strategy involves the use of single doses of Bi-213 labeled antibody or other ligands. However, these methods alone do not enable the use of alpha particle emitting constructs because they fail to take into account the necessity for high specific activity ligands in order for specific cell kill to occur. This necessity arises from the particular nature of the alpha particle emission, i.e., high linear energy transfer and extremely short range, which does not exist for the beta or gamma emissions that have previously been used therapeutically in humans. As a consequence, whereas a beta emitting therapeutic antibody which kills in a field of radiation may be effective at any number of specific activities, an alpha-emitting antibody will only be effective if a minimum of one atom can be delivered to each cell, resulting in at least 1 alpha track through the cell.
The prior art is deficient, first, in understanding the importance of and requirement for the high specific activity in the process of cell kill with an alpha particle, and second, in understanding how one might kill tumors with more than a small number of cells. Therefore, the prior art is deficient in the lack of effective means of killing large tumors (>1 mm in diameter) or other cells involved in human or animal diseases using the high specific alpha-emitting constructs. The present invention fulfills this long-standing need and desire in the art.